Ly6C^hi monocytes regulate T cell responses in viral hepatitis

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Abstract

Viral hepatitis remains a global health challenge despite recent progress in the development of more effective therapies. Although virus-specific CD8⁺ and CD4⁺ T cell responses are essential for viral clearance, it remains largely unknown what regulates T cell–mediated viral clearance. Thus, a better understanding of the regulation of anti-viral T cell immunity would be critical for the design of more effective therapies for viral hepatitis. Using a model of adenovirus-induced hepatitis, here we showed that adenoviral infection induced recruitment of Ly6C^hi monocytes to the liver in a CCR2-dependent manner. These recruited Ly6C^hi monocytes suppressed CD8⁺ and CD4⁺ T cell responses to adenoviral infection, leading to a delay in viral clearance. In vivo depletion of Ly6C^hi monocytes markedly enhanced anti-viral T cell responses and promoted viral clearance. Mechanistically, we showed that induction of iNOS and the production of NO by Ly6C^hi monocytes are critical for the suppression of T cell responses. In addition, a contact-dependent mechanism mediated by PD-1 and PD-L1 interaction is also required for T cell suppression by Ly6C^hi monocytes. These findings suggest a critical role for Ly6C^hi monocytes in the regulation of T cell immunity in viral hepatitis and may provide new insights into development of more effective therapies for treating viral hepatitis based on targeting the immunosuppressing monocytes.

Authors

Jiangao Zhu, Huiyao Chen, Xiaopei Huang, Songfu Jiang, Yiping Yang